Clinical Infectious Diseases IDSA GUIDELINE

Clinical Infectious Diseases IDSA GUIDELINE Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Tamar F. Barlam, 1,a Sara E. Cosgrove, 2,a Lilian M. Abbo, 3 Conan MacDougall, 4 Audrey N. Schuetz, 5 Edward J. Septimus, 6 Arjun Srinivasan, 7 Timothy H. Dellit, 8 Yngve T. Falck-Ytter, 9 Neil O. Fishman, 10 Cindy W. Hamilton, 11 Timothy C. Jenkins, 12 Pamela A. Lipsett, 13 Preeti N. Malani, 14 Larissa S. May, 15 Gregory J. Moran, 16 Melinda M. Neuhauser, 17 Jason G. Newland, 18 Christopher A. Ohl, 19 Matthew H. Samore, 20 Susan K. Seo, 21 and Kavita K. Trivedi 22 1 Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts; 2 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland; 3 Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida; 4 Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco; 5 Department of Medicine, Weill Cornell Medical Center/New York Presbyterian Hospital, New York, New York; 6 Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Houston; 7 Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; 8 Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle; 9 Department of Medicine, Case Western Reserve University and Veterans Affairs Medical Center, Cleveland, Ohio; 10 Department of Medicine, University of Pennsylvania Health System, Philadelphia; 11 Hamilton House, Virginia Beach, Virginia; 12 Division of Infectious Diseases, Denver Health, Denver, Colorado; 13 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Schools of Medicine and Nursing, Baltimore, Maryland; 14 Division of Infectious Diseases, University of Michigan Health System, Ann Arbor; 15 Department of Emergency Medicine, University of California, Davis; 16 Department of Emergency Medicine, David Geffen School of Medicine, University of California, Los Angeles Medical Center, Sylmar; 17 Department of Veterans Affairs, Hines, Illinois; 18 Department of Pediatrics, Washington University School of Medicine in St. Louis, Missouri; 19 Section on Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 20 Department of Veterans Affairs and University of Utah, Salt Lake City; 21 Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, New York; and 22 Trivedi Consults, LLC, Berkeley, California Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics. Keywords. antibiotic stewardship; antibiotic stewardship programs; antibiotics; implementation. EXECUTIVE SUMMARY Antibiotic stewardship has been defined in a consensus statement from the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), and the Pediatric Infectious Diseases Society (PIDS) as coordinated interventions designed to improve and measure the appropriate use of [antibiotic] agents by promoting the selection of the optimal [antibiotic] drug regimen including dosing, duration of therapy, and route of administration [1]. The benefits of antibiotic stewardship include improved patient outcomes, reduced adverse events including Clostridium difficile infection (CDI), improvement in rates of antibiotic susceptibilities to targeted antibiotics, and optimization of resource utilization across the continuum of care. IDSA and SHEA strongly believe that Received 22 February 2016; accepted 23 February 2016. a T. F. B. and S. E. C. contributed equally to this work as co-chairs. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant clinician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the clinician in the light of each patient s individual circumstances. Correspondence: T. F. Barlam, Boston Medical Center, One Boston Medical Center Place, Boston, MA 02118 (tamar.barlam@bmc.org). Clinical Infectious Diseases 2016;62(10):1197 202 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. DOI: 10.1093/cid/ciw217 antibiotic stewardship programs (ASPs) are best led by infectious disease physicians with additional stewardship training. Summarized below are the IDSA/SHEA recommendations for implementing an ASP. The expert panel followed a process used in the development of other IDSA guidelines, which included a systematic weighting of the strength of recommendation and quality of evidence using the GRADE (Grading of s Assessment, Development and Evaluation) system (Figure 1) [2 5]. A detailed description of the methods, background, and evidence summaries that support each of the recommendations can be found online in the full text of the guidelines. For the purposes of this guideline, the term antibiotic will be used instead of antimicrobial and should be considered synonymous. RECOMMENDATIONS FOR IMPLEMENTING AN ANTIBIOTIC STEWARDSHIP PROGRAM Interventions I. Does the Use of Preauthorization and/or Prospective Audit and Feedback Interventions by ASPs Improve Antibiotic Utilization and Patient Outcomes? 1. We recommend preauthorization and/or prospective audit and feedback over no such interventions (strong recommendation, moderate-quality evidence). Guideline for Implementing an Antibiotic Stewardship Program CID 2016:62 (15 May) 1197

Figure 1. Approach and implications to rating the quality of evidence and strength of recommendations using the Grading of s Assessment, Development and Evaluation (GRADE) methodology (unrestricted use of this figure granted by the US GRADE Network). Comment: Preauthorization and/or prospective audit and feedback improve antibiotic use and are a core component of any stewardship program. Programs should decide whether to include one strategy or a combination of both strategies based on the availability of facility-specific resources for consistent implementation, but some implementation is essential. II. Is Didactic Education a Useful Antibiotic Stewardship Intervention for Reducing Inappropriate Antibiotic Use? 2. We suggest against relying solely on didactic educational materials for stewardship (weak recommendation, lowquality evidence). Comment: Passive educational activities, such as lectures or informational pamphlets, should be used to complement other stewardship activities. Academic medical centers and teaching hospitals should integrate education on fundamental antibiotic stewardship principles into their preclinical and clinical curricula. III. Should ASPs Develop and Implement Facility-Specific Clinical Practice Guidelines for Common Infectious Diseases Syndromes to Improve Antibiotic Utilization and Patient Outcomes? 3. We suggest ASPs develop facility-specific clinical practice guidelines coupled with a dissemination and implementation strategy (weak recommendation, Comment: Facility-specific clinical practice guidelines and algorithms can be an effective way to standardize prescribing practices based on local epidemiology. ASPs should develop those guidelines, when feasible, for common infectious diseases syndromes. In addition, ASPs should be involved in writing clinical pathways, guidelines, and order sets that address antibiotic use and are developed within other departments at their facility. 1198 CID 2016:62 (15 May) Barlam et al

IV. Should ASPs Implement Interventions to Improve Antibiotic Use and Clinical Outcomes That Target Patients With Specific Infectious Diseases Syndromes? 4. We suggest ASPs implement interventions to improve antibiotic use and clinical outcomes that target patients with specific infectious diseases syndromes (weak recommendation, Comment: ASP interventions for patients with specific infectious diseases syndromes can be an effective way to improve prescribing because the message can be focused, clinical guidelines and algorithms reinforced, and sustainability improved. ASPs should regularly evaluate areas for which targeted interventions are needed and adapt their activities accordingly. This approach is most useful if the ASP has a reliable way to identify patients appropriate for review. technology resources are readily available. However, computerized surveillance systems that synthesize data from the electronic health record and other data sources can streamline the work of ASPs by identifying opportunities for interventions. VIII. Should ASPs Implement Strategies That Promote Cycling or Mixing in Antibiotic Selection to Reduce Antibiotic Resistance? 8. We suggest against the use of antibiotic cycling as a stewardship strategy (weak recommendation, Comment: Available data do not support the use of antibiotic cycling as an ASP strategy, and further research is unlikely to change that conclusion. Because clinical data are sparse for antibiotic mixing, we cannot give any recommendation about its utility. V. Should ASPs Implement Interventions Designed to Reduce the Use of Antibiotics Associated With a High Risk of CDI? 5. We recommend antibiotic stewardship interventions designed to reduce the use of antibiotics associated with a high risk of CDI compared with no such intervention (strong recommendation, moderate-quality evidence). Comment: The goal of reducing CDI is a high priority for all ASPs and should be taken into consideration when crafting stewardship interventions. VI. Do Strategies to Encourage Prescriber-Led Review of Appropriateness of Antibiotic Regimens, in the Absence of Direct Input From an Antibiotic Stewardship Team, Improve Antibiotic Prescribing? 6. We suggest the use of strategies (eg, antibiotic time-outs, stop orders) to encourage prescribers to perform routine review of antibiotic regimens to improve antibiotic prescribing (weak recommendation, Comment: Published data on prescriber-led antibiotic review are limited, but successful programs appear to require a methodology that includes persuasive or enforced prompting. Without such a mechanism, these interventions are likely to have minimal impact. VII. Should Computerized Clinical Decision Support Systems Integrated Into the Electronic Health Record at the Time of Prescribing be Incorporated as Part of ASPs to Improve Antibiotic Prescribing? 7. We suggest incorporation of computerized clinical decision support at the time of prescribing into ASPs (weak recommendation, moderate-quality evidence). Comment: Computerized clinical decision support for prescribers should only be implemented if information Optimization IX. In Hospitalized Patients Requiring Intravenous (IV) Antibiotics, Does a Dedicated Pharmacokinetic (PK) Monitoring and Adjustment Program Lead to Improved Clinical Outcomes and Reduced Costs? s 9. We recommend that hospitals implement PK monitoring and adjustment programs for aminoglycosides (strong recommendation, moderate-quality evidence). 10. We suggest that hospitals implement PK monitoring and adjustment programs for vancomycin (weak recommendation, Comment: PK monitoring and adjustment programs can reduce costs and decrease adverse effects. The ASP should encourage implementation and provide support for training and assessment of competencies. The conduct of those programs should be integrated into routine pharmacy activities. X. In Hospitalized Patients, Should ASPs Advocate for Alternative Dosing Strategies Based on PK/Pharmacodynamic Principles to Improve Outcomes and Decrease Costs for Broad-Spectrum ß-Lactams and Vancomycin? 11. In hospitalized patients, we suggest ASPs advocate for the use of alternative dosing strategies vs standard dosing for broad-spectrum β-lactams to decrease costs (weak recommendation, Comment: Although data for improved outcomes for broad-spectrum β-lactam dosing with this approach are still limited, these interventions are associated with antibiotic cost savings. ASPs should consider implementation but must take into account logistical issues such as nursing and pharmacy education and need for dedicated IV access. Considering the limited evidence, we cannot give any Guideline for Implementing an Antibiotic Stewardship Program CID 2016:62 (15 May) 1199

recommendation about the utility of alternative dosing strategies for vancomycin. XI. Should ASPs Implement Interventions to Increase Use of Oral Antibiotics as a Strategy to Improve Outcomes or Decrease Costs? 12. We recommend ASPs implement programs to increase both appropriate use of oral antibiotics for initial therapy and the timely transition of patients from IV to oral antibiotics (strong recommendation, moderate-quality evidence). Comment: Programs to increase the appropriate use of oral antibiotics can reduce costs and length of hospital stay. IV-to-oral conversion of the same antibiotic is less complicated than other strategies and is applicable to many healthcare settings. The conduct of those programs should be integrated into routine pharmacy activities. ASPs should implement strategies to assess patients who can safely complete therapy with an oral regimen to reduce the need for IV catheters and to avoid outpatient parenteral therapy. XII. In Patients With a Reported History of ß-Lactam Allergy, Should ASPs Facilitate Initiatives to Implement Allergy Assessments With the Goal of Improved Use of First-Line Antibiotics? 13. In patients with a history of β-lactam allergy, we suggest that ASPs promote allergy assessments and penicillin (PCN) skin testing when appropriate (weak recommendation, Comment: Allergy assessments and PCN skin testing can enhance use of first-line agents, but it is largely unstudied as a primary ASP intervention; however, ASPs should promote such assessments with providers. In facilities with appropriate resources for skin testing, the ASPs should actively work to develop testing and treatment strategies with allergists. XIII. Should ASPs Implement Interventions to Reduce Antibiotic Therapy to the Shortest Effective Duration? 14. We recommend that ASPs implement guidelines and strategies to reduce antibiotic therapy to the shortest effective duration (strong recommendation, moderate-quality evidence). Comment: Recommending a duration of therapy based on patient-specific factors is an important activity for ASPs. Suitable approaches include developing written guidelines with specific suggestions for duration, including duration of therapy recommendations as part of the preauthorization or prospective audit and feedback process, or specifying duration at the time of antibiotic ordering (eg, through an electronic order entry system). Microbiology and Laboratory Diagnostics XIV. Should ASPs Work With the Microbiology Laboratory to Develop Stratified Antibiograms, Compared With Nonstratified Antibiograms? 15. We suggest development of stratified antibiograms over solely relying on nonstratified antibiograms to assist ASPs in developing guidelines for empiric therapy (weak recommendation, Comment: Although there is limited evidence at this time that stratified antibiograms (eg, by location or age) lead to improved empiric antibiotic therapy, stratification can expose important differences in susceptibility, which can help ASPs develop optimized treatment recommendations and guidelines. XV. Should ASPs Work With the Microbiology Laboratory to Perform Selective or Cascade Reporting of Antibiotic Susceptibility Test Results? 16. We suggest selective and cascade reporting of antibiotics over reporting of all tested antibiotics (weak recommendation, Comment: Although data are limited that demonstrate direct impact of those strategies on prescribing, some form of selective or cascaded reporting is reasonable. After implementation, ASPs should review prescribing to ensure there are no unintended consequences. XVI. Should ASPs Advocate for Use of Rapid Viral Testing for Respiratory Pathogens to Reduce the Use of Inappropriate Antibiotics? 17. We suggest the use of rapid viral testing for respiratory pathogens to reduce the use of inappropriate antibiotics (weak recommendation, Comment: Although rapid viral testing has the potential to reduce inappropriate use of antibiotics, results have been inconsistent. Few studies have been performed to assess whether active ASP intervention would improve those results. XVII. Should ASPs Advocate for Rapid Diagnostic Testing on Blood Specimens to Optimize Antibiotic Therapy and Improve Clinical Outcomes? 18. We suggest rapid diagnostic testing in addition to conventional culture and routine reporting on blood specimens if combined with active ASP support and interpretation (weak recommendation, moderate-quality evidence). Comment: Availability of rapid diagnostic tests is expected to increase; thus, ASPs must develop processes and interventions to assist clinicians in interpreting and responding appropriately to results. 1200 CID 2016:62 (15 May) Barlam et al

XVIII. In Adults in Intensive Care Units (ICUs) With Suspected Infection, Should ASPs Advocate Procalcitonin (PCT) Testing as an Intervention to Decrease Antibiotic Use? 19. In adults in ICUs with suspected infection, we suggest the use of serial PCT measurements as an ASP intervention to decrease antibiotic use (weak recommendation, moderatequality evidence). Comment: Although randomized trials, primarily in Europe, have shown reduction in antibiotic use through implementation of PCT algorithms in the ICU, similar data are lacking for other regions including the United States where the patterns of antibiotic prescribing and approach to stewardship may differ. If implemented, each ASP must develop processes and guidelines to assist clinicians in interpreting and responding appropriately to results, and must determine if this intervention is the best use of its time and resources. XIX. In Patients With Hematologic Malignancy, Should ASPs Advocate for Incorporation of Nonculture-Based Fungal Markers in Interventions to Optimize Antifungal Use? 20. In patients with hematologic malignancy at risk of contracting invasive fungal disease (IFD), we suggest incorporating nonculture-based fungal markers in ASP interventions to optimize antifungal use (weak recommendation, low-quality evidence). Comment: ASPs with an existing intervention to optimize antifungal use in patients with hematologic malignancy can consider algorithms incorporating nonculture-based fungal markers. Those interventions must be done in close collaboration with the primary teams (eg, hematology-oncology). Antibiotic stewards must develop expertise in antifungal therapy and fungal diagnostics for the programs to be successful. The value of those markers for interventions in other populations has not been demonstrated. that data with clinicians to help inform their practice. Although rates of CDI or antibiotic resistance may not reflect ASP impact (because those outcomes are affected by patient population, infection control, and other factors), those outcomes may also be used for measurement of targeted interventions. XXI. What is the Best Measure of Expenditures on Antibiotics to Assess the Impact of ASPs and Interventions? 22. We recommend measuring antibiotic costs based on prescriptions or administrations instead of purchasing data (good practice recommendation). XXII. What Measures Best Reflect the Impact of Interventions to Improve Antibiotic Use and Clinical Outcomes in Patients With Specific Infectious Diseases Syndromes? 23. Measures that consider the goals and size of the syndromespecific intervention should be used (good practice recommendation). Special Populations XXIII. Should ASPs Develop Facility-Specific Clinical Guidelines for Management of Fever and Neutropenia (F&N) in Hematology- Oncology Patients to Reduce Unnecessary Antibiotic Use and Improve Outcomes? 24. We suggest ASPs develop facility-specific guidelines for F&N management in hematology-oncology patients over no such approach (weak recommendation, Comment: Clinical guidelines with an implementation and dissemination strategy can be successfully used in the care of cancer patients with F&N and are strongly encouraged. Measurement XX. Which Overall Measures Best Reflect the Impact of ASPs and Their Interventions? 21. We suggest monitoring antibiotic use as measured by days of therapy (DOTs) in preference to defined daily dose (DDD) (weak recommendation, Comment: Every ASP must measure antibiotic use, stratified by antibiotic. DOTs are preferred, but DDDs remain an alternative for sites that cannot obtain patient-level antibiotic use data. ASPs should consider measurement of appropriate antibiotic use within their own institutions by examining compliance with local or national guidelines, particularly when assessing results of a targeted intervention, and share XXIV. In Immunocompromised Patients Receiving Antifungal Therapy, do Interventions by ASPs Improve Utilization and Outcomes? 25. We suggest implementation of ASP interventions to improve the appropriate prescribing of antifungal treatment in immunocompromised patients (weak recommendation, Comment: In facilities with large immunocompromised patient populations, ASP interventions targeting antifungal therapy can show benefit. Those interventions must be done in close collaboration with the primary teams (eg hematology-oncology, solid organ transplant providers). Antibiotic stewards must develop expertise in antifungal therapy and fungal diagnostics for the programs to be successful. Guideline for Implementing an Antibiotic Stewardship Program CID 2016:62 (15 May) 1201

XXV. In Residents of Nursing Homes and Skilled Nursing Facilities, do Antibiotic Stewardship Strategies Decrease Unnecessary Use of Antibiotics and Improve Clinical Outcomes? 26. In nursing homes and skilled nursing facilities, we suggest implementation of antibiotic stewardship strategies to decrease unnecessary use of antibiotics (good practice recommendation). Comment: Implementing ASPs at nursing homes and skilled nursing facilities is important and must involve point-of-care providers to be successful. The traditional physician pharmacist team may not be available on-site, and facilities might need to investigate other approaches to review and optimize antibiotic use, such as obtaining infectious diseases expertise through telemedicine consultation. XXVI. In Neonatal Intensive Care Units (NICUs), do Antibiotic Stewardship Interventions Reduce Inappropriate Antibiotic Use and/or Resistance? 27. We suggest implementation of antibiotic stewardship interventions to reduce inappropriate antibiotic use and/or resistance in the NICU (good practice recommendation). XXVII. Should ASPs Implement Interventions to Reduce Antibiotic Therapy in Terminally Ill Patients? 28. In terminally ill patients, we suggest ASPs provide support to clinical care providers in decisions related to antibiotic treatment (good practice recommendation). Notes Acknowledgments. The expert panel expresses its gratitude to Drs Elizabeth Dodds Ashley, Annie Wong-Beringer, and Stan Deresinski for their thoughtful reviews of earlier drafts of the guideline. The panel greatly appreciates the work of Charles B. Wessels and Michele Klein Fedyshin of the Health Sciences Library System of the University of Pittsburgh for the development and execution of the systematic literature searches for this guideline, and Jennifer J. Padberg, MPH, for her administrative assistance throughout the guideline development process. Financial support. Support for these guidelines was provided by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America. Potential conflicts of interest. The following list is a reflection of what has been reported to IDSA. To provide thorough transparency, IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest is determined by a review process that includes assessment by the Standards and Practice Guidelines Committee (SPGC) chair, the SPGC liaison to the development panel, and the board of directors liaison to the SPGC, and, if necessary, the Conflicts of Interest (COI) Task Force of the Board. This assessment of disclosed relationships for possible COI will be based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. S. E. C. has received grants from Pfizer Grants for Learning and Change, and personal fees from Novartis, outside the submitted work. C. M. has received personal fees from Actavis Pharmaceuticals and grants from Cubist Pharmaceuticals, outside the submitted work. A. N. S. has received nonfinancial support from Bruker Diagnostics, outside the submitted work. C. W. H. has received payments for manuscript preparation from IDSA, during the conduct of the work, and payments from Cardeas, Johnson & Johnson, and Sanofi Aventis, outside the submitted work. T. C. J. has been a member of an advisory committee for Durata Therapeutics, outside the submitted work. P. A. L. has received personal fees from JAMA Surgery and Oakstone General Surgery, outside the submitted work. L. S. M. has received grants and nonfinancial support from, and has served on advisory boards for, Cepheid and Durata, and has received honoraria from Alere, outside the submitted work. G. J. M. has received grants from Cempra Pharmaceuticals, Cerexa, and AstraZeneca, and has participated as coauthor on a manuscript for Cubist Pharmaceuticals, outside the submitted work. J. G. N. has served as a consultant for RPS Diagnostics and has received grants from Pfizer, outside the submitted work. C. A. O. has received personal fees from Astellas and Bayer Pharmaceuticals, outside the submitted work. K. K. T. has received personal fees from Premier, Diatherix, the American Institutes of Research, University of Rochester, and Dignity Health, and has received grants from Pew Charitable Trusts, the CDC Foundation, and the Association of State and Territorial Health Officials, outside the submitted work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Fishman N. Policy statement on amtimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012; 33:322 7. 2. Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to recommendations. BMJ 2008; 336:1049 51. 3. Guyatt GH, Oxman AD, Kunz R, et al. Incorporating considerations of resources use into grading recommendations. BMJ 2008; 336:1170 3. 4. Jaeschke R, Guyatt GH, Dellinger P, et al. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ 2008; 337:a744. 5. US GRADE Network. Approach and implications to rating the quality of evidence and strength of recommendations using the GRADE methodology, 2015. Available at: http://www.gradeworkinggroup.org/. Accessed 17 July 2015. 1202 CID 2016:62 (15 May) Barlam et al